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Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants
GILBERT, M. E. Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants. Presented at Neurobehavioral Toxicology Society, Teratology Meeting, San Diego, CA, June 25 - 29, 2011.
The degree of thyroid hormone insufficiency induced by environmental contaminants is typically not severe, yet impact of modest fluctuations in hormone has not been adequately addressed in animal models
Inadequate levels of thyroid hormone during critical developmental periods lead to stunted growth, mental retardation, and neurological 'cretinism'. Animal models of developmental thyroid hormone deficiency mirror well the impact of severe insults to the thyroid system. However, it has become clear from studies in humans that even modest perturbations of the thyroid axis may not be benign. A large number of environmental contaminants reduce circulating levels of thyroid hormone, and do so by their interaction with a variety of target sites. The degree of thyroid hormone insufficiency induced by environmental contaminants is typically not severe, yet impact of modest fluctuations in hormone has not been adequately addressed in animal models. We have investigated the dose-response relationships of thyroid hormone disruption induced during pregnancy and lactation in rats exposed to the thyroid hormone synthesis inhibitor, propylthiouracil (PTU), dietary iodine deficiency, and the environmental contaminant, ammonium perchlorate. These treatments were delivered to produce graded levels of hormone reduction and offspring were examined on a number of cognitive endpoints, neuroanatomical, genomic, and neurophysiological parameters. We found that severe hormone depletion is not necessary to alter brain development. Gene expression changes in cortex and hippocampus in PTU-and perchlorate-exposed pups were associated with mild alterations in serum hormones. Our work and others has demonstrated cell fate specificity and neuronal migration are disrupted by PTU, a related synthesis inhibitor, methimazole, and iodine deficiency. Electrophysiological impairments in hippocampal synaptic transmission in adult offspring were evident in all three models, and in our hands, were the most reliable in identifying brain dysfunction. Simple behavioral tasks (Morris water maze and fear conditioning) have not proven very sensitive in identifying neurodevelopmental insults at low levels of hormone insufficiency. In some cases, dam serum hormone levels were more predictive of neurophysiological and molecular deficits than hormones measured in pups. We conclude that long-term functional deficits accompany moderate levels of thyroid hormone insufficiency induced by a number of means. It is likely that the negative impact of axenobiotic-induced perturbation in thyroid hormone status will be exacerbated under conditions of iodine deficiency and this is currently under study. (Does not reflect US EPA policy)